The causal structure of a system imposes constraints on the joint probability distribution of variables that can be generated by the system. Archetypal constraints consist of conditional ...independencies between variables. However, particularly in the presence of hidden variables, many causal structures are compatible with the same set of independencies inferred from the marginal distributions of observed variables. Additional constraints allow further testing for the compatibility of data with specific causal structures. An existing family of causally informative inequalities compares the information about a set of target variables contained in a collection of variables, with a sum of the information contained in different groups defined as subsets of that collection. While procedures to identify the form of these groups-decomposition inequalities have been previously derived, we substantially enlarge the applicability of the framework. We derive groups-decomposition inequalities subject to weaker independence conditions, with weaker requirements in the configuration of the groups, and additionally allowing for conditioning sets. Furthermore, we show how constraints with higher inferential power may be derived with collections that include hidden variables, and then converted into testable constraints using data processing inequalities. For this purpose, we apply the standard data processing inequality of conditional mutual information and derive an analogous property for a measure of conditional unique information recently introduced to separate redundant, synergistic, and unique contributions to the information that a set of variables has about a target.
Homeward Nguyen, Julia K
Palliative Medicine Reports,
04/2022, Letnik:
3, Številka:
1
Journal Article
Recenzirano
Odprti dostop
I've heard that it's the young deaths that kill you. JC was 17 years old, a native son of California. At 5 foot 9 inches and 210 lbs, he was a growing oak, with leaves green and vibrant from every ...angle, with the promise of mightiness. But in the towering shadows of outspread branches, a voracious beetle (chondrogenic osteosarcoma) was boring through the bark and into the concentric rings of the wood underneath. After undergoing a hemipelvectomy and assault by chemotherapy and then radiation, JC learned that the silent invader had proliferated and advanced into his femoral, sacral, and pelvic bones. We had taken care of him for two months. This included providing parenteral nutrition, and the usual care that would be expected to stay the effects of the well?you know?the thing that should not be named. He was treated until he was admitted for bacterial and fungal sepsis at a local Children's Hospital in June. When he returned to us in February, he was on hospice care for intractable pain. I knew it was the beginning of the end. His initial intravenous morphine 10?mg/h patient-controlled analgesia had escalated from 40?mg/hr to 80?mg/hr to 100?mg/hr to 300?mg/hr in just 10 days. He was completely bedridden and also on a dartboard of medications.? Although JC received temporary relief from multiple boluses and could find sleep in fleeting moments, the effects did not last for more than two to three hours at a time. He would wake up screaming, shaking, and jerking in excruciatingly sharp shooting pain emanating from his hip, pelvis, and back. His pain was aggravated by movement and quantified using the Visual Analog Scale as being 7/10 to 10/10 most of the time. The disease was silent no more. His mother sobbed on the phone, ?No mother should have to outlive her child and see so much pain.? It was so hard on her, a single mom trying to make ends meet. She was so exhausted down to her roots. JC was angry at the world and depressed in the moment. The puppy he had received as a birthday gift to welcome him home had just died of ?kennel cough.? She needed JC's grandmother to help with the caregiving. I remember her choked-up voice before she hung up, ?Please help me, please help us.? That was it, a simple plea for a not-so-simple situation. I called the hospice physician who was relieved to hear from me. She had JC's mother's permission to control his pain at any cost. Could we buy time with a trial of decreasing the morphine dosing, hoping for a possible opioid-induced hyperalgesia during this tense environment? She hesitated. ?It's going to be a hard sell; mom is expecting more, not less. And we will be in the same situation, or worse if it does not work as planned.? ?How about opioid rotation to intravenous hydromorphone?? I asked. ?No go?he had hallucinations prior to discharge home,? she responded. I groaned inwardly knowing there was no easy solution. In our experience with end-stage illness and extreme dosing, the line between disease progression and opioid tolerance was often blurred. I proceeded down my mental checklist. He was on adjuvants, check. But even with antimetics he was having nausea that limited his ability to regularly ingest medications. My shoulder muscles tightened. ?How much time do you think he has left?? I tentatively asked. ?He's young, with good cardiac function, but bowel movements have decreased to every five days. His will to live is fading fast.? Add ketamine, I thought. Y-site not tested; and the admixture was intravenous (IV) compatible. He had a double lumen peripherally inserted central catheter (PICC), and his other line was occupied by parenteral nutrition. What concentration would I compound to make it work? Did I need another peripheral or subcutaneous line? Would that be enough to work quickly? My mind raced to keep up with my pounding heart. I took a deep breath to calm my heartbeat and reminded myself to focus. I offered up a ketamine?fentanyl?midazolam (KFM) cocktail letting her know that our local team had no previous actual experience with this off-label approach. I felt like Hermione Granger conjuring from the Book of Potions. Any purported outcomes were based on medical literature in hospitalized older adults of variable dosing ranges and testimonials from other acute medical oncology centers.1 The consensus was that managing bone cancer pain in the home was a beast that enraged unique inflammatory and worsening neurological changes. We understood this battle. It was a fight not to save JC from dying young but a fight to honor his dying well. JC's physician, nurse, and I held a teleconference to plan the initiation of the cocktail, scheduled for the following morning. Overnight, after-hours staff on call had increased his morphine to 500?mg/h. At 10:00 in the morning, the nurse started ketamine 2?mg/mL?fentanyl 5 mcg/mL?midazolam 0.1?mg/mL (KFM) combination through a CADD? Prizm pump. The starting dose was 10?mL/h with 5?mL every 15 minutes as needed for breakthrough pain. We decreased morphine by 100?mg/h concurrently and nursing assessed him every hour with orders to call the physician to titrate to comfort. The effects were immediate. By the next day at 2:00 pm, morphine was discontinued. JC was comfortable and responding well to boluses. The involuntary jerking had stopped and he only had some pain when turning. Methadone, lorazepam, and haloperidol were held. For the next nine days, we titrated the KFM. I took all calls related to JC's care and raced to keep abreast of providing the short-term stability medication. I wanted to stay ahead of our pharmacy's supply given the current background of national supply chain-related shortages. Multiple one-liter bags were delivered three times a week. I was concerned about the volume of fluid being provided and recommended separating the triple mix for improved stability and ease, titrating the ketamine separately. She agreed. We would use the Y-site for the ketamine and infuse the fentanyl?midazolam with another pump. We had limited stability data for concentrating the cocktail so parenteral nutrition volume was decreased. At first, JC was able to sleep more peacefully for only a few hours. Gradually the duration of his sleep increased until he was able to sleep for the whole night within five days of starting KFM. JC no longer screamed. He no longer moaned. There was no more grimacing, no more restlessness, and no more agitation. His grandmother reported to me, ?He has nothing to complain about!? JC was on ketamine 120?mg/h/fentanyl 300 mcg/h/midazolam 6?mg/h when I received the last phone call. It had been 16 days after initiation, for a total of 26 days under our care. His nurse reported, as a small measure of success, that he was finally able to enjoy a popsicle before going to sleep. When he passed away, his face was peaceful. His grandmother and mother were grateful, with tears streaming down their faces, and thankful for the nurse at the home and thankful for all that had been done for JC. I exhaled deeply. As I drove home in a black sea of blood red taillights, the glimmering night stars were obscured by billowy clouds. Cool moist air blew hair against my face. I felt the sensation, but I was numb. What was I feeling, sorrow or joy? By naming the fear, would it loosen its grip on me? What had transpired? Experience was a brutal task master, tasting salty and bittersweet at the same time. The slight humming buzz in my head grew louder like a street market of voices jostling to be heard before erupting. JC had given me knowledge as a gift in exchange of his life. We were bound inextricably through the unveiling of this mysterious cosmic eternal truth. We all are comprised of physical matter and to exist without hope is a bleak prospect. How do we answer the call to matter to others during our time? Although JC's story occurred over 15 years ago, it was a transformative experience that nearly crushed me as a new practitioner. Triumph of hope can be a blinding impetus for therapeutic interventions. And so at what point might a clinician decide that the alleviating powers of medications have reached their limit? Our medical center has since developed evidence-based guidelines to navigate those necessary conversations for home palliative management of intractable agitation and suffering and malignant bowel obstruction. Moreover, our team has elected to voluntarily participate in medical aid in dying as legalized in California. Although the optimism connected to new therapies is sometime unsustained, clearly we can explore therapies previously abandoned as too aggressive or invasive as they may provide succor for death and dying in the home. JC's legacy is a reminder of the value of death and for me, continues to fuel the beacon for performance improvement in end-of-life care.2 Disclaimer All views expressed by the author are solely her opinion and do not reflect the opinions of SCPMG or Kaiser Permanente. SCPMG has not reviewed this submission and makes no representation regarding its accuracy or completeness.
Childhood abuse has been associated with poor health outcomes in adulthood. However, the physiologic pathways by which abuse is linked to health are not fully elucidated. Inflammation plays a ...significant role in the pathophysiology of multiple chronic diseases. We tested whether childhood trauma exposure was related to increased systemic inflammation in midlife women.
Participants were 304 nonsmoking perimenopausal and postmenopausal women aged 40 to 60 years and free of cardiovascular disease. They completed questionnaires assessing psychosocial and behavioral factors, including childhood trauma, anthropometric measures, wrist actigraphy sleep measurements, and a fasting blood draw for inflammatory markers high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6). Associations between childhood trauma and inflammatory markers were tested in linear regression models controlling for age, race/ethnicity, education, body mass index, anti-inflammatory medication use, and alcohol consumption. Other covariates considered included sleep continuity and depressive symptoms.
A total of 44.8% of the sample experienced at least one type of childhood abuse/neglect. Women with a history of emotional abuse had higher IL-6 levels than women without this history in multivariate models (
= 0.077, standard error = 0.032,
= 0.017). Results were not accounted for by covariates and persisted additionally controlling for depressive symptoms and sleep. Childhood abuse/neglect was not related to hsCRP.
Childhood emotional abuse was associated with higher levels of IL-6 in midlife women. Assessing childhood trauma exposure along with inflammatory markers may be important for the development of prevention strategies at midlife to prevent chronic diseases later in life.
Pancreatic neuroendocrine tumors (PanNETs) are a type of pancreatic cancer with limited therapeutic options. Consequently, most patients with advanced disease die from tumor progression. Current ...evidence indicates that a subset of cancer cells is responsible for tumor development, metastasis, and recurrence, and targeting these tumor-initiating cells is necessary to eradicate tumors. However, tumorinitiating cells and the biological processes that promote pathogenesis remain largely uncharacterized in PanNETs. Here we profile primary and metastatic tumors from an index patient and demonstrate that MET proto-oncogene activation is important for tumor growth in PanNET xenograft models. We identify a highly tumorigenic cell population within several independent surgically acquired PanNETs characterized by increased cell-surface protein CD90 expression and aldehyde dehydrogenase A1 (ALDHA1) activity, and provide in vitro and in vivo evidence for their stem-like properties. We performed proteomic profiling of 332 antigens in two cell lines and four primary tumors, and showed that CD47, a cell-surface protein that acts as a “don’t eat me” signal co-opted by cancers to evade innate immune surveillance, is ubiquitously expressed. Moreover, CD47 coexpresses with MET and is enriched in CD90hi cells. Furthermore, blocking CD47 signaling promotes engulfment of tumor cells by macrophages in vitro and inhibits xenograft tumor growth, prevents metastases, and prolongs survival in vivo.
Single-cell RNA sequencing (scRNA-seq) is the leading technique for characterizing the transcriptomes of individual cells in a sample. The latest protocols are scalable to thousands of cells and are ...being used to compile cell atlases of tissues, organs and organisms. However, the protocols differ substantially with respect to their RNA capture efficiency, bias, scale and costs, and their relative advantages for different applications are unclear. In the present study, we generated benchmark datasets to systematically evaluate protocols in terms of their power to comprehensively describe cell types and states. We performed a multicenter study comparing 13 commonly used scRNA-seq and single-nucleus RNA-seq protocols applied to a heterogeneous reference sample resource. Comparative analysis revealed marked differences in protocol performance. The protocols differed in library complexity and their ability to detect cell-type markers, impacting their predictive value and suitability for integration into reference cell atlases. These results provide guidance both for individual researchers and for consortium projects such as the Human Cell Atlas.
Acute stroke leads to the activation of myeloid cells. These cells express adhesion molecules and transmigrate to the brain, thereby aggravating injury. Chronically after stroke, repair processes, ...including angiogenesis, are activated and enhance post-stroke recovery. Activated myeloid cells express CD13, which facilitates their migration into the site of injury. However, angiogenic blood vessels which play a role in recovery also express CD13. Overall, the specific contribution of CD13 to acute and chronic stroke outcomes is unknown.
CD13 expression was estimated in both mice and humans after the ischemic stroke. Young (8-12 weeks) male wild-type and global CD13 knockout (KO) mice were used for this study. Mice underwent 60 min of middle cerebral artery occlusion (MCAO) followed by reperfusion. For acute studies, the mice were euthanized at either 24- or 72 h post-stroke. For chronic studies, the Y-maze, Barnes maze, and the open field were performed on day 7 and day 28 post-stroke. Mice were euthanized at day 30 post-stroke and the brains were collected for assessment of inflammation, white matter injury, tissue loss, and angiogenesis. Flow cytometry was performed on days 3 and 7 post-stroke to quantify infiltrated monocytes and neutrophils and CXCL12/CXCR4 signaling.
Brain CD13 expression and infiltrated CD13
monocytes and neutrophils increased acutely after the stroke. The brain CD13
lectin
blood vessels increased on day 15 after the stroke. Similarly, an increase in the percentage area CD13 was observed in human stroke patients at the subacute time after stroke. Deletion of CD13 resulted in reduced infarct volume and improved neurological recovery after acute stroke. However, CD13KO mice had significantly worse memory deficits, amplified gliosis, and white matter damage compared to wild-type animals at chronic time points. CD13-deficient mice had an increased percentage of CXCL12
cells but a reduced percentage of CXCR4
cells and decreased angiogenesis at day 30 post-stroke.
CD13 is involved in the trans-migration of monocytes and neutrophils after stroke, and acutely, led to decreased infarct size and improved behavioral outcomes. However, loss of CD13 led to reductions in post-stroke angiogenesis by reducing CXCL12/CXCR4 signaling.
Mitophagy is a critical mitochondrial quality control process that selectively removes dysfunctional or excess mitochondria through the autophagy-lysosome system. The process is tightly controlled to ...ensure cellular and physiological homeostasis. Insufficient mitophagy can result in failure to remove damaged mitochondria and consequent cellular degeneration, but it is equally important to appropriately restrain mitophagy to prevent excessive mitochondrial depletion. Here, we discuss our recent discovery that the SKP1-CUL1-F-box (SCF)-FBXL4 (F-box and leucine-rich repeat protein 4) E3 ubiquitin ligase localizes to the mitochondrial outer membrane, where it constitutively mediates the ubiquitination and degradation of BNIP3L/NIX and BNIP3 mitophagy receptors to suppress mitophagy. The post-translational regulation of BNIP3L and BNIP3 is disrupted in mitochondrial DNA depletion syndrome 13 (MTDPS13), a multi-systemic disorder caused by mutations in the FBXL4 gene and characterized by elevated mitophagy and mitochondrial DNA/mtDNA depletion in patient fibroblasts. Our results demonstrate that mitophagy is not solely stimulated in response to specific conditions but is instead also actively suppressed through the continuous degradation of BNIP3L and BNIP3 mediated by the SCF-FBXL4 ubiquitin ligase. Thus, cellular conditions or signaling events that prevent the FBXL4-mediated turnover of BNIP3L and BNIP3 on specific mitochondria are expected to facilitate their selective removal.
To maintain both mitochondrial quality and quantity, cells selectively remove damaged or excessive mitochondria through mitophagy, which is a specialised form of autophagy. Mitophagy is induced in ...response to diverse conditions, including hypoxia, cellular differentiation and mitochondrial damage. However, the mechanisms that govern the removal of specific dysfunctional mitochondria under steady‐state conditions to fine‐tune mitochondrial content are not well understood. Here, we report that SCFFBXL4, an SKP1/CUL1/F‐box protein ubiquitin ligase complex, localises to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that the pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13) do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism whereby FBXL4 actively suppresses mitophagy by preventing NIX and BNIP3 accumulation. We propose that the dysregulation of NIX and BNIP3 turnover causes excessive basal mitophagy in FBXL4‐associated mtDNA depletion syndrome.
Synopsis
How are specific dysfunctional mitochondria removed under steady‐state conditions? This study shows that FBXL4, encoded by the gene mutated in encephalopathic mtDNA depletion syndrome (MTDPS13), suppresses steady‐state mitophagy through ubiquitylation and turnover of NIX and BNIP3 mitophagy receptors.
SCF ubiquitin ligase receptor FBXL4 localises to the mitochondrial outer membrane to mediate the ubiquitylation and degradation of BNIP3 and NIX mitophagy receptors.
FBXL4 deficiency results in elevated mitophagy due to the stabilisation of NIX/BNIP3 mitophagy receptors.
MTDPS13‐associated variants in FBXL4 are less efficient at mediating the turnover of BNIP3 and NIX and mitophagy restriction.
Steady‐state ubiquitylation and turnover of NIX and BNIP3 limits basal mitophagy and is dysregulated in MTDPS13, accounting for the elevated mitophagy associated with this encephalopathic mtDNA depletion syndrome.
Urinary tract infections (UTI) are often over-diagnosed and over-treated, which can induce and select for resistant pathogens. After observing wide-spread outpatient use of ertapenem, a ...broad-spectrum antibiotic, a structured antimicrobial stewardship initiative (ASI) to improve appropriate antimicrobial prescribing was undertaken. ASI objectives were to achieve a goal of reducing ertapenem utilization for extended spectrum beta lactamase Enterobacteriaceae (ESBL-EB) UTI by 10% and evaluate the clinical outcomes associated with the ASI.
A pre-to-post cohort study was conducted at a single-center integrated healthcare system between November 1, 2014 and February 26, 2017. An intensive, 90-day, pharmacist-driven, structured ASI was implemented between November 1, 2015 and January 29, 2016. Female patients aged ≥18 years who were treated for an uncomplicated, ESBL-EB urinary tract infection (UTI) were included. Primary outcome was clinical resolution defined as cure, persistence, relapse and recurrence. Secondary outcome measured was monthly ertapenem use expressed as number of days of therapy (DOT)/1000 adjusted patient days (APD). Segmented regression analysis for interrupted time series was performed to estimate ASI intervention effect.
A total of 184 patients were included in the study. Ertapenem utilization decreased from 0.0145 DOT/1000 APD in Nov. 2014 to 0.0078 DOT/1000 APD Feb. 2017(p < 0.01). The mean ertapenem DOT declined 19% overall from the pre vs. post intervention periods (32 vs 26, p < 0.01). Frequency of recurrent UTIs between treatments did not significantly differ and no adverse effects were reported in patients treated with aminoglycosides.
A structured ASI for uncomplicated ESBL-EB UTI was associated with a clinically meaningful decrease in ertapenem utilization and once-daily, 5-day aminoglycoside treatment was well-tolerated.
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